Decision Making: a Theoretical Review.

Decision-making is a crucial skill that has a central role in everyday life and is necessary for adaptation to the environment and autonomy. It is the ability to choose between two or more options, and it has been studied through several theoretical approaches and by different disciplines. In this overview article, we contend a theoretical review regarding most theorizing and research on decision-making. Specifically, we focused on different levels of analyses, including different theoretical approaches and neuropsychological aspects. Moreover, common methodological measures adopted to study decision-making were reported. This theoretical review emphasizes multiple levels of analysis and aims to summarize evidence regarding this fundamental human process. Although several aspects of the field are reported, more features of decision-making process remain uncertain and need to be clarified. Further experimental studies are necessary for understanding this process better and for integrating and refining the existing theories.

Heart Rate Variability and Decision-Making: Autonomic Responses in Making Decisions.

Decision-making is one of the most crucial cognitive processes in daily life. An adaptable, rapid, and flexible decision requires integration between brain and body. Heart rate variability (HRV) indexes this brain-body connection and appears to be related to cognitive performance. However, its relationship with decision-making is poorly analyzed. This study investigates the relationship between HRV and the decision-making process, assessed through the Iowa Gambling Task (IGT). One hundred and thirty healthy university students (mean age = 23.35 ± 2.50) participated in the study. According to IGT performance, they were divided into high decision-makers (n = 79) and low decision-makers (n = 51). Heart rate variability was measured in the resting, reactivity (i.e., during IGT), and recovery phases. Higher vagally mediated HRV (vmHRV; indexed in frequency domain measures) was evidenced in good decision-makers in the resting, reactivity, and recovery phases. During the task, a higher vagal modulation after a first evaluation was highlighted in good decision-makers. In conclusion, HRV proves to be a valid index of inhibitory circuit functioning in the prefrontal cortex. The relationship with cognitive functions was also confirmed, considering the ability to inhibit disadvantageous responses and make better decisions.

Novel inhibitors of Rad6 ubiquitin conjugating enzyme: design, synthesis, identification, and functional characterization.

Protein ubiquitination is important for cell signaling, DNA repair, and proteasomal degradation, and it is not surprising that alterations in ubiquitination occur frequently in cancer. Ubiquitin-conjugating enzymes (E2) mediate ubiquitination by selective interactions with ubiquitin-activating (E1) and ubiquitin ligase (E3) enzymes, and thus selective E2 small molecule inhibitor (SMI) will provide specificity unattainable with proteasome inhibitors. Here we describe synthesis and functional characterization of the first SMIs of human E2 Rad6B, a fundamental component of translesion synthesis DNA repair. A pharmacophore model for consensus E2 ubiquitin-binding sites was generated for virtual screening to identify E2 inhibitor candidates. Twelve triazine (TZ) analogs screened in silico by molecular docking to the Rad6B X-ray structure were verified by their effect on Rad6B ubiquitination of histone H2A. TZs #8 and 9 docked to the Rad6B catalytic site with highest complementarity. TZs #1, 2, 8, and 9 inhibited Rad6B-ubiquitin thioester formation and subsequent ubiquitin transfer to histone H2A. SMI #9 inhibition of Rad6 was selective as BCA2 ubiquitination by E2 UbcH5 was unaffected by SMI #9. SMI #9 more potently inhibited proliferation, colony formation, and migration than SMI #8, and induced MDA-MB-231 breast cancer cell G2-M arrest and apoptosis. Ubiquitination assays using Rad6 immunoprecipitated from SMI #8- or 9-treated cells confirmed inhibition of endogenous Rad6 activity. Consistent with our previous data showing Rad6B-mediated polyubiquitination stabilizes ß-catenin, MDA-MB-231 treatment with SMIs #8 or 9 decreased ß-catenin protein levels. Together these results describe identification of the first Rad6 SMIs.

Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization.

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low µM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.